title: Scavenger receptor CD36 is essential for the cerebrovascular oxidative stress and neurovascular dysfunction induced by amyloid-beta.
abstract: Increasing evidence indicates that cerebrovascular dysfunction plays a pathogenic role in Alzheimer's dementia (AD). Amyloid-β (Aβ), a peptide central to the pathogenesis of AD, has profound vascular effects mediated, for the most part, by reactive oxygen species produced by the enzyme NADPH oxidase. The mechanisms linking Aβ to NADPH oxidase-dependent vascular oxidative stress have not been identified, however. We report that the scavenger receptor CD36, a membrane glycoprotein that binds Aβ, is essential for the vascular oxidative stress and neurovascular dysfunction induced by Aβ1-40. Thus, topical application of Aβ1-40 onto the somatosensory cortex attenuates the increase in cerebral blood flow elicited by neural activity or by endothelium-dependent vasodilators in WT mice but not in CD36-null mice (CD36(0/0)). The cerebrovascular effects of infusion of Aβ1-40 into cerebral arteries are not observed in mice pretreated with CD36 blocking antibodies or in CD36(0/0) mice. Furthermore, CD36 deficiency prevents the neurovascular dysfunction observed in transgenic mice overexpressing the Swedish mutation of the amyloid precursor protein Tg2576 despite elevated levels of brain Aβ1-40. CD36 is also required for the vascular oxidative stress induced by exogenous Aβ1-40 or observed in Tg2576 mice. These observations establish CD36 as a key link between Aβ1-40 and the NADPH oxidase-dependent vascular oxidative stress underlying the neurovascular dysfunction and suggest that CD36 is a potential therapeutical target to counteract the cerebrovascular dysfunction associated with Aβ.
authors.affiliation: Division of Neurobiology, Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, NY 10065, USA.
authors.forename: Laibaik
authors.initials: L
authors.lastname: Park
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Joan
authors.initials: J
authors.lastname: Zhou
authors.forename: Rose
authors.initials: R
authors.lastname: Pitstick
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: Previti
authors.forename: Linda
authors.initials: L
authors.lastname: Younkin
authors.forename: Steven G
authors.initials: SG
authors.lastname: Younkin
authors.forename: William E
authors.initials: WE
authors.lastname: Van Nostrand
authors.forename: Sunghee
authors.initials: S
authors.lastname: Cho
authors.forename: Josef
authors.initials: J
authors.lastname: Anrather
authors.forename: George A
authors.initials: GA
authors.lastname: Carlson
authors.forename: Costantino
authors.initials: C
authors.lastname: Iadecola
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000235:genetics; D002561:Cerebrovascular Disorders / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D013003:Somatosensory Cortex / Q000378:metabolism / Q000503:physiopathology
chemical_list: D016229:Amyloid beta-Peptides; D057134:Antibodies, Neutralizing; D018955:CD36 Antigens; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D019255:NADPH Oxidases